Emerging therapeutics targeting castration-resistant prostate cancer: the AR-mageddon of tumor epithelial-mesenchymal transition

Abstract

Advanced prostate cancer will claim nearly 30,000 lives among men in the USA in the year 2013. Most of these will be castration-resistant prostate cancers that are not responsive to traditional therapeutic modalities, and there is no available regimen that fully eradicates metastatic disease. This poses a significant clinical challenge for practitioners and has stimulated the development of novel agents that target these castration-resistant tumor cells. Development of metastatic prostate cancer is orchestrated by multiple signaling pathways that regulate cell survival, apoptosis, anoikis, epithelial-mesenchymal transition (EMT), invasion, the androgen signaling axis and angiogenesis. Disruption of the mechanisms underlying these processes is critical for development of agents that can target otherwise resistant tumor cells. Insights into the mechanisms by which rounds of EMT/mesenchymal-epithelial transition conversions facilitate the progression of localized prostate carcinomas to advanced metastatic and castration-resistant disease emerge as attractive targets for drug development. In this review, the authors discuss the current understanding of therapeutic resistance in castration-resistant prostate cancer with focus on the androgen receptor signaling axis and EMT. Novel therapeutic approaches targeting critical players of both pathways as well as the results from ongoing clinical trials will be discussed in this review.

Keywords: adrenoreceptor antagonists; androgen receptor; angiogenesis; anoikis; castration resistance; epithelial–mesenchymal transition; metastasis; novel therapeutic strategies; prostate cancer.